Patients with previously treated renal cell carcinoma (RCC) had a median progression-free survival (PFS) of 5.6 months, median overall survival (OS) of 28.9 months, and objective response rate of 15% with the monoclonal antibody atezolizumab, which targets the programmed death-1 pathway, including its ligand (PD-1/PD-L1). The agent had similar activity in patients whose disease was refractory to a vascular endothelial growth (VEGF) factor inhibitor or who had no prior exposure to a VEGF inhibitor.

The incidence of grade 3 treatment-related adverse events was 17% among 70 evaluable patients, most often fatigue, David F. McDermott, MD, of Beth Israel Deaconess Medical Center in Boston, and co-authors reported online in the Journal of Clinical Oncology.

"Current treatments for metastatic renal cell carcinoma (RCC) target the VEGF and mammalian target of rapamycin pathways," the authors noted. "Despite their clinical benefit, resistance often develops within the first year of treatment, which underscores a need for therapies that produce durable tumor responses with acceptable toxicity."

Drugs that target PD-1/PD-L1 have demonstrated activity across a wide range of solid tumors, including RCC. As previously reported, nivolumab (Opdivo), one of the two approved PD-1/PD-L1 agents, recently became the first agent to produce a survival advantage in advanced/metastatic RCC versus standard care, everolimus (Afinitor) in that case.

The promising activity and generally favorable safety profile of anti-PD-1/PD-L1 therapies provided a rationale for continued investigation in advanced and metastatic RCC.

McDermott and co-authors reported findings from a phase Ia trial involving 70 patients with previously treated advanced or metastatic RCC, 63 of whom had clear-cell histology. The study population was enriched with patients whose tumors tested positive for patients with tumors that expressed PD-L1. By immunohistochemistry (IHC), 23 patients had no detectable PD-L1 expression and 23 had IHC 2/3 expression.

Atezolizumab led to an objective response rate of 15% in 63 evaluable patients, including 18% in the subgroup with any detectable PD-L1 expression (IHC 1-3) versus 9% in the IHC 0 subgroup. The highest response rates were observed in patients with a high Fuhrman grade or sarcomatoid features (22%), grade 4 tumors (25%), or sarcomatoid histology (33%). Overall, 46% of patients had some degree of tumor shrinkage, the authors reported.

The median overall survival of 28.9 months included 28.8 months for patients with IHC 0 tumors versus not yet reached for the IHC 1/2/3 subgroup and 20.6 months for patients with prior anti-VEGF inhibitor therapy versus 29.1 months for those without.

Atezolizumab is currently being investigated in combination therapy for patients with previously untreated metastatic RCC to clarify the role the new anti-PD-L1 antibody might have in advanced or metastatic RCC, the authors noted.

The study involved a heterogeneous patient population, complicating efforts to interpret the results, according to Toni Choueiri, MD, Dana-Farber Cancer Institute in Boston. Nonetheless, he noted that previously treated patients in the nivolumab study had a median overall survival of 25 months compared with 20.6 months in the atezolizumab trial.

To better tease out this particular PD-L1's activity, Choueiri felt it might be better compared to findings from the previously cited study in which nivolumab, another PD-L1 antibody inhibitor, was compared to everolimus in previously treated advanced RCC patients. In this study, median OS was 25 months while in the current study, median OS was 20.6 months in a comparable group of previously treated patients, as Choueiri observed.

"This is closer to the median overall investigators saw for everolimus in the comparative trial, which was 19.6 months," Choueiri told MedPage Today. The overall response rate with atezolizumab was also lower at 15% compared with 25% for nivolumab, he added.

"Results from the current study are not as encouraging as I would have liked them to be," Choueiri added. "Having said that, the money may be in future studies among patients with positive biomarkers or high-grade tumors."

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